People with coronary artery disease face an elevated risk for shingles because aberrant immune cells dial down the body’s immune response to viral pathogens, Stanford research shows.

Now, Stanford University School of Medicine researchers have traced the connection to a defective immune cell’s sweet tooth.

In a study published online June 12 in the Journal of Clinical Investigation, the researchers learned that a set of immune cells whose aberrantly large appetite for glucose predisposes people to this heart condition also disables the immune response to viral infections — and does so using the same immune–response–derailing technique often employed by cancer cells.

Our increasing vulnerability to shingles as we age speaks to our immune system not being as capable as when we’re younger, said Cornelia Weyand, MD, professor and chief of immunology and rheumatology. “But how this would be related to heart disease has been an open question, until now,” she said.

In about 20 percent of shingles cases, the excruciating pain persists long after the rash clears up, said Weyand, the study’s senior author. The lead authors are postdoctoral scholar Ryu Watanabe, MD, PhD, and former postdoctoral scholar Tsuyoshi Shirai, MD, PhD, now at Tokohu University in Japan.

“Coronary artery disease patients’ glucose–guzzling macrophages, it turns out, exert the same paralyzing effect on T cells that cancers cells do, in much the same way,” Weyand said.

The investigators obtained blood and tissue samples from 113 patients with coronary artery disease who had sustained at least one heart attack and from 109 demographically matched healthy control subjects. From participants’ blood samples, the scientists extracted cells called monocytes that begin life in the bone marrow, circulate in blood and, on taking up residence in a tissue, mature into full–blown macrophages. The scientists induced this maturation in culture.

“Your T cells’ ability to stave off shingles is a good proxy for your overall ability to fight off new pathogens, the re–emergence of old ones or cancer,” said Weyand. T cells targeting varicella zoster get aroused on contact with macrophages displaying pieces of this virus on their surfaces. So, the researchers fed viral bits to monocyte–derived macrophages from either the patients or the control subjects, and then gauged reactions of T cells incubated in a dish with these cells. One–third as many T cells exposed to virus–displaying macrophages from the patients mounted a reaction compared with T cells exposed to macrophages from the age–matched control subjects.

Antibodies that interfere with the PD1/PD–L1 checkpoint happen to be easy for researchers to come by, as these antibodies are in wide use today as cancer treatments. Adding such antibodies to the mix substantially restored T cells’ erstwhile–diminished responsiveness to the patients’ shingles–virus–primed macrophages.

Disabling the ability of the patients’ macrophages to metabolize sugar likewise restored their capacity to incite T cell action. In particular, a small–molecule compound called ML265, which is now in clinical cancer trials, largely reversed PD–L1 overexpression on the surface of patients’ macrophages. ML265 works by maintaining the appropriate configuration of an enzyme involved in glucose metabolism. In the presence of too much glucose–breakdown activity, Weyand’s lab has previously shown, this enzyme suffers a breakdown of its own, initiating the chain reaction that causes macrophages to start spewing out pro–inflammatory chemicals.

In the new study, the scientists demonstrated that the enzyme’s glucose–induced malfunction also sets off a different complicated biochemical cascade involving overproduction of a substance called BMP4. This, in turn, raises PD–L1 expr